My H.I.V. patients for the most part are hale and hearty thanks to three decades of intense and excellent research and billions of dollars invested. Many of my ME/CFS patients, on the other hand, are terribly ill and unable to work or participate in the care of their families. I split my clinical time between the two illnesses, and I can tell you if I had to choose between the two illnesses (in 2009) I would rather have H.I.V.

According to Nancy Klimas research into male pattern baldness gets six times more federal funding in the US than research into ME/CFS. It’s not so strange, then, that it takes time to find good answers to the ME/CFS enigma.

I have written many blog posts at my Norwegian blog De Bortgjemte about positive developments in the ME/CFS research field, and those definitely exist. But it most certainly is not a booming field with increasing budgets. And that is the main reason we do not know more about disease mechanisms or effective treatments.

For 25 years ME/CFS has been near the bottom of the list when it comes to funding for research. Perhaps Klimas refers to an exceptionally meagre year when she mentions the sum of $3 million, but in the larger perspective it is all the same. Over time the level of funding for ME/CFS research is deplorable.

The following graph shows NIH funding for ME/CFS research compared to three comparable diseases, MS, arthritis and lupus:

These numbers say it all. NIH spends around $115 million on MS research every year. For ME/CFS, the number is $5 million. (Source: NIH Categorical Spending).

One single year of MS research equals about 23 years of ME/CFS research. That is just about all ME/CFS research ever done.

The same comparison with arthritis shows that one year of arthritis research translates into 50 years of ME/CFS research. And one year of NIH spending on HIV/AIDS is the equivalent of about 600 years’ worth of ME/CFS grants.

Still, no cure has been found for HIV/AIDS. We do not know why people develop MS. And for patients with RA, treatment is still focused on symptom relief.

Looking at these facts it is no wonder we know so little about ME/CFS. The government institutions have decided this is where we should be at.

In HIV, MS and RA, researchers have developed effective treatments. We are far from knowing everything, but we know a lot. Much more than just a few years ago. Due to research funding. Billions of it.

So, is there a coherence between the level of funding and how many people are afflicted by each disease?

The following graph shows the estimated prevalence of the diseases mentioned above:

ME/CFS afflicts far more people than the autoimmune disease lupus. Still, NIH allocates 20 times more funding for research into lupus.

I wish research for all these diseases to thrive. As much as possible. I do not want funds to be taken from anybody. But I think we should take note of what must be called unfair differences. Should not ME/CFS patients also be allowed to benefit from public research spending? Especially since the ME/CFS research field has been chronically underfinanced for the last quarter of a century.

Several studies show that the functional status in ME/CFS is lower than in many other chronic diseases. There can be no doubt that this is a group of severely ill patients. But just as there is no coherence between prevalence and research funds, there is no coherence between disease burden and funding budgets either.

In the 1990s it was revealed that the CDC spent money earmarked for ME/CFS on other programs and activities. When a whistle blower tried to report this internally he was, according to the Washington Times, “basically told to shut up”. An audit revealed that CDC for four years spent 40-60% of the funds earmarked for ME/CFS on unrelated matters. Several CDC staff members had given false testimony to Congress about the actual use of the money.

«CDC officials provided inaccurate information to Congress regarding the use of CFS funds, and have not supported the CFS program to the extent recommended and encouraged by Congress.»
From the official audit report from 1999.

Based on all of this it is reasonable to assert that ME/CFS research has been given extremely low priority. At times it even looks like it has been actively obstructed by the government institutions appointed to administer research funds.

It is therefore not surprising that the following picture emerges when comparing the number of published studies in s0me of the diseases I have used as comparisons in this blog post:

The graph shows how many studies are published each year world wide (Source: PubMed). While around 200 research articles on ME/CFS were published in 2013, that same year brought almost 4000 articles on MS. The total amount of published studies in the ME/CFS field is roughly 5000. That is the grand total.

This is what needs to change. Because this is also where answers will be found. To why people get ill. And how we can help them.

(This blog post was originally published in Norwegian at debortgjemte.com in May 2014. It was translated into English by Anne Örtegren after she asked my permission to do so. For a long time I have had an intention of publishing more in English, but unfortunately I have not had the capacity to do so. So big thanks to Anne for the translation!)

“They soon found that new ideas aren’t always welcome in science – even if the old ones aren’t working.”Switch off, switch on, The National, 2009.

2004: Patient zero

Anne Katrine walks into the Cancer Department at Haukeland University Hospital in Bergen in 2004 to get treatment against the lymphoma the doctors discovered one year earlier. After four rounds of chemotherapy the cancer seemed to be beaten, but suddenly it came back and she is in for her second treatment regimen.

Anne Katrine also has ME/CFS since she suddenly fell ill with mononucleosis in 1997. For several years she had mostly been housebound with muscle pain, problems with sleep and great cognitive difficulties. An overwhelming fatigue and malaise has made her unable to leave the house for more than short periods of time.

Five weeks after starting the new treatment against lymphoma, something unexpected happens. Suddenly she notices a marked improvement in all the ME/CFS symptoms that she has endured for more than seven years. She has never before experienced anything like this. Her teenage son had one time told her that he was not sure if he could manage to live with someone as sick as his mother. Now, they were able to go to Turkey together for the holidays.

But suddenly it all comes back. The headache, the aching muscles, the cognitive decline and the devastating fatigue and malaise. Back to scratch.

“When you had cancer, mom, we had the best dinners ever,” Anne Katrines daughter tells her after the relapse.

Sitting in his office at Haukeland University Hospital, cancer specialist Øystein Fluge scratches the back of his head, puzzled. What really happened to his patient Anne Katrine?

For years to come he cannot forget what he saw during these months in 2004.

2009: Pioneering

In October 2009 I sat in a small office at Haukeland University Hospital in Bergen, a city on the west coast of Norway. I remember it well. The two doctors enthusiastic telling of their surprising tale. I was in the very beginning of researching my book about ME/CFS when I came across a small pilot study from the very same people I was meeting for the first time this day.

Even then, without the extensive knowledge about ME/CFS that I have now, I remember thinking: If this turns out to be true, it will change everything.

It was a beautiful sunny day, with snow covering the peaks around Bergen. On my way to the meeting with professor Olav Mella and doctor Øystein Fluge, I saw signs pointing the public to the mass vaccinations against the swine flu. In a few weeks Norwegian authorities had spent more money on buying vaccines than everything the American government had spent on ME/CFS research for the last 25 years.

I remember seeing that as a telling comparison pointing towards a still grim future for ME/CFS. But now, I was wondering if these two doctors story could be a turning point. After 25 years of controversies, lack of funding, maltreatment, ridicule and dashed hopes. Could this be the game changer?

Dr Fluge was talking about Anne Katrines remarkable story of recovery from most of her ME/CFS symptoms, and after those months she had never let Fluge off the hook. She begged him to find out what had happened. And in the end, Fluge and Olav Mella, the head of the Cancer Departement at the hospital, decides to give it a try even though they have never before worked with ME/CFS, barely heard of it.

“Our starting point was: Could this be an autoimmune disease? And if so, could it be that it was methotrexate in Anne Katrines treatment that was working on her ME/CFS symptoms”, said Fluge.

Methotrexate is a medication which dampens the immune response. It is used in large doses in some cancer treatments, but it is also used in smaller doses against different autoimmune diseases, for example rheumatoid arthritis. Anne Katrine had gone through three different courses of cancer treatment, but only with one of them did she experience a near resolution of her ME/CFS symptoms. In that treatment she got methotrexate, something she did not get during the other treatments.

“We could not know if this hypothesis was right, but our idea was to try to treat CFS with Rituximab, which is a medication that works directly on the B-cells in the immune system,” said Fluge.

Like methotrexate, Rituximab is a medication that dampens the immune response, but through a different mechanism. It basically wipes the B-cells out for a few months before they slowly grow back. Both of these medications are used in the treatment of cancer and autoimmune diseases. In 2007, Fluge and Mella decided to do a small pilot study on three ME/CFS patients. One of the three patients they contacted was Svein.

“Before Olav Mella called me, I remember I discussed with my wife how long I would manage to go on with this disease,” said Svein when I asked his story in a phone interview.

He worked at the local hospital, but after a serious viral infection ten years earlier he never recovered. For a long time he tried to stay at work, but in the end had to give it up.

“I have been so ill that I was bedridden and had to get help to get to the toilet. But of course, I still hope to get back to work some day,” Svein said.

Six weeks after his first infusion with Rituximab something happened. In just a few days Svein experienced major improvement in all ME/CFS symptoms.

“My father in law has a cabin, and it is situated just a hundred meters from the road from where we had to walk. Usually my stay at that cabin had been just managing to get there, and then I had to lie on the couch or the bed during the whole stay. Now I went skiing with my kids,” said Svein.

He could take one-hour walks and started to do carpentry on his house. Myalgic pain was markedly reduced. Cognitive functions improved remarkably, and he could now read a whole book without interruption. The hypersensitivity to noise decreased. He and his wife confirmed that family life had improved considerably.

“After my first treatment I finished two books in a weekend. Before treatment I could not even read two pages,” said Svein.

But after ten weeks of major improvement Svein crashed. Back to a life within the four walls of his house. All the symptoms came back as fast as they had gone away. He received a second treatment course, and the same thing happened. Major improvement after six weeks, then ten weeks with maintained improvement, and then a crash.

In February 2009 he got a new infusion.

“Then I had the best effect so far, and it lasted even longer. I started doing carpentry on the house, made a new roof and new walls, put down cables. I throw myself at these kinds of projects when I feel better, because I feel there is so much I have undone. As soon as my body functions again, I’m ready,” said Svein.

Before treatment with Rituximab, Svein had only been able to watch pictures of his kid’s activities outside the house.

“That feels terrible. When I get this treatment I manage to participate. It is like being brought back to life again,” said Svein.

The two other patients in the pilot study, one of them Anne Katrine, and the other a woman in her early twenties, had similar major improvements after Rituximab treatment. Mella and Fluge were themselves surprised when they saw the astounding pilot results, where the patients at times experienced near resolution of all of their symptoms.

“Then we felt that we were touching a central mechanism in the disease,” said Fluge back in 2009.

They started a double blinded, placebo controlled and randomized study on Rituximab in 30 ME/CFS patients – what is called a RCT. Placebo controlled means that the patients are divided into two groups – 15 got placebo (salt water) and 15 got Rituximab. Double blinded means that neither the patients, nor the researchers, know who gets real drugs and who does not. Randomized means that it is random which group the 30 patients end up in. This is considered the gold standard in medical research on drugs.

At my first meeting with the two doctors that day in 2009 none of them knew if their study would turn out positive. They did not yet know which patients got the drug and who got placebo.

I followed Mella and Fluge closely the next two years. Ups and downs. Uncertainty and promise. And now we all know: new hope. Let us take a leap to October 2011.

2011: Praise

“It’s the most encouraging drug result so far in the history of this disease. Although it’s a small trial, it’s produced dramatic results,” said Charles Shepherd, MD and medical advisor to Britains biggest patient association for ME/CFS, to New Scientist in October 2011.

The Norwegian Rituximab study had just been published in PLoS ONE, and it generated a massive amount of media coverage. “Immune system defect may cause ME” reported BBC. “Cancer drug can help chronic fatigue” was the headline in Europes leading news magazine Der Spiegel.

Never before had a study on a drug in ME/CFS had such promising results.

The study on 30 patients showed that 10 out of 15 patients (67 %) got a significant improvement from the cancer drug Rituximab which wipes out most of the B-cells in the immune system. 9 out of the 10 responders got a “major improvement” according to the paper. In the placebo group only 2 out of 15 (13 %) got a significant improvement. The result was 10-2 between the groups. Or 9-1 if you only look at “major improvers”. It turned out that most of the responders, unlike two out of three pilot patients who were early responders, started their improvement as late as 3-7 months after the infusion with the drug. Another significant finding was that most patients relapsed when the effect of the B-cell depletion wore off, which is consistent with the effect of such treatment in some autoimmune disesases. “Thus, we believe that B-cell depletion targets a central player in the pathogenesis of the CFS disease, directly or indirectly”, the study authors wrote in their paper.

The director of Haukeland University hospital, Stener Kvinnsland, who was not directly involved in the study, said to the Norwegian broadcaster TV2 that he ”had a strong feeling that this was a breakthrough”. Dr. Kvinnsland is one of Norways most respected cancer researchers with a solid track record, and to a Norwegian newspaper he said that the Rituximab finding was one of the most exciting things he had followed in his professional career.

Professor Carmen Scheibenbogen, Deputy Director of the Institute of Medical Immunology at the Charité University Hospital in Berlin, described the results of the study as a possible breakthrough. “This is a very important first step. For the first time, a therapeutic study has been conducted with medication that was originally applied to the immune system, and which proved effective for a majority of the patients”, she told bto.no.

In Norway, a country where ME/CFS has generated a lot of media attention the last few years, the Rituximab study led to a media blitz. For several days the media reported on the study, the lack of good care for the patients and all the broken promises about better services for ME/CFS patients from the government and the responsible health care providers.

It was like Rituximab was a tipping point for not longer being able to give the impression that this disease was not real, or that it was mainly a psychosomatic problem. Because how do you argue against a big gun cancer drug? In a way, Rituximab did not just heal some of the study participants, it also healed the self-respect of thousands of Norwegian ME/CFS patients who finally experienced something else than suspicion and disbelief.

In a rare public statement the National Institutes of Health in Norway even apologized to the patients for the lack of services and years of mismanagement.

Before the Rituximab study hit the news, I called Sheba Medical Center in Tel Aviv to talk to the Israeli scientist and world renowned expert on autoimmunity, Yehuda Shoenfeld. He is editor in chief of Autoimmunity Reviews and has written several books and published hundreds of scientific articles on autoimmunity. In a review article in 2009 he wrote that recent findings in ME/CFS “points toward an ongoing autoimmune phenomenon in such patients that, although not fully understood, is likely to be enhanced by the presence of certain infectious agents and other adjuvants”.

“I cannot say for sure that this is an autoimmune disease, but CFS has a lot in common with this group of diseases”, a busy Shoenfeld told me over the phone.

At this time he had only seen Mella and Fluges pilot study on three patients, but he said that what they reported there looks much the same as what you see when you use Rituximab in diseases like rheumatoid arthritis and SLE (lupus). Then he said that if they got positive results in a controlled study, it would indicate that a central mechanism in ME/CFS will be found in the immune system.

I asked him if that would be surprising to him.

“No, not to me, but it depends who you ask. I have the idea that CFS belongs in this group of autoimmune patients”, said Shoenfeld.

I have since talked to several international ME/CFS experts, all of them enthusiastic about the Rituximab results. At last year’s Invest in ME conference I sat down with one of the most respected ME/CFS-clinicians, Daniel Peterson, and asked him his thoughts.

– I think it is a crucial step forward, he told me.

And then he went on to say that he had seen effects of Rituximab himself. Several of his ME/CFS patients had developed lymphoma and therefore got treated with Rituximab, one of them for several years.

– And after starting treatment his ME/CFS symptoms disappeared, said Peterson.

The future: Persistence

Of course, like everything in ME/CFS, no promising study without controversy. So the study in PLoS ONE also met criticism right away. This is science after all. Controversy is the rule, and more so in ME/CFS than anything else. A group of prominent ME/CFS researchers commented the study at the PLoS ONE pages, implying the results were oversold and with methodological flaws, and they challenged the conclusions. Then one of the world leading authorities on Rituximab quickly commented on a lot of flaws in the critics own criticism. Professor Jonathan Edwards from University College London said their criticism “contains several errors”, and went on to say that the “trial’s authors give the account that is by far the most consistent with the data”.

“In the end I think we have to find the cause behind the disease, or else no one will believe us. If we are right, which I think we are, we will make it. In a few years I think the scientific community will have the answer”, said Fluge responding to some of the doubting critics.

It is important to acknowledge, like Fluge and Mella themselves have repeatedly said, that there is need for bigger studies before concluding on Rituximab and ME/CFS. And this study, like every innovative scientific study, also needs to be subject for criticism and disagreements to make headway for what we all want in the end – the truth. So why did I mention Jonathan Edwards? I did because he has been here, right where ME/CFS is now with Rituximab, just with a different disease. And Jonathan Edwards won the dispute. No one ridicules his ideas anymore.

In the 1990s Edwards, together with another British scientist, Geraldine Cambridge, came up with a theory about possible B-cell involvement in rheumatoid arthritis (RA). They met a cold shoulder from the rest of the research community. The importance of T-cells was then the only accepted theory in RA, and therefore most in the medical community automatically thought that the theory of Edwards and Cambridge were not worth pursuing.

“When the patients’ B cells disappeared, so did most of their arthritis,” Edwards told New Scientist in 2001. Three of the five patients remained well for a longer period, while symptoms of the disease came back in two patients once their B cells returned.

After years of unproductive battling trying to get this groundbreaking idea of the importance of B-cells in RA acknowledged in the medical community, Edwards talked to the press, and the story made headlines. Something which of course made some of his critics even more critical, but it worked. Finally they got funding for a big study on Rituximab in RA, and in 2004 the results were published in the prestigious New England Journal of Medicine. The result? Rituximab turned out to be a superior treatment in the study, and suddenly B-cells were on everybody’s lips.

“With so few patients, it’s hardly definitive proof of a cure. Yet it is just the situation Prof Edwards and Dr Cambridge found themselves in a decade ago. CFS sufferers must be hoping medical researchers are not about to repeat history by rejecting these intriguing findings out of hand – despite not having any better ideas themselves.”

Against the odds, Jonathan Edwards and his colleagues turned the whole field of RA around through pure persistence. He definitely knows that paradigm shifts do happen in medicine. No stranger from controversy, maybe Edwards gets that old feeling back reading the PLoS ONE study from Mella and Fluge, tempting him to have his say in public. Maybe he knows that the Norwegian scientists are in for a hell of a ride.

And maybe, just maybe, he wants them to win too.

(Jorgen Jelstad is a Norwegian journalist and author of the documentary book “The Hidden Ones: and how ME came to be the most controversial disease of our time”. The book is so far only available in Norwegian – named “De Bortgjemte”. This article was printed in Invest in MEs conference magazine for the 2012 Invest in ME conference. Here is the conference magazine in full.)

Everybody in Norway now knows the word Rituximab and everybody knows that something exciting has been going on in the hallways of Haukeland University hospital in Bergen. One of Norways two major TV-channels, TV2, has given the Rituximab-study just published in PLoS ONE a massive amount of coverage. It has also been reported in BBC, Der Spiegel (the biggest and leading news magazine in Europe), the respected scientific magazine New Scientist and others.

I’m a journalist and I have a mother with a diagnosis of ME/CFS. The last two and a half years I have been working on a book about the disease: “The Hidden – and how ME/CFS became the most controversial disease of our time”. It’s a book about the history, politics and controversies and what consequences all of this has had for the patients trying to live with this disease in health care and society. The book was just published by one of Norways biggest publishers Cappelen Damm (it is only available in Norwegian language).

I have done hundreds of hours with interviews with ME/CFS-researchers and clinicians in Norway and in the international scientific community, I have been to several ME/CFS-conferences, I have met loads of patients and carers, advocates and politicians, lawyers and nurses – and I have been reading thousands of pages in research papers, reports, public documents, books etc.

I have also been following closely the work of dr. Øystein Fluge and dr. Olav Mella since late 2009 – long before they even knew if their study on Rituximab would be positive. A big part of the book documents the whole story behind this research.

From all my work, I know that the Rituximab-study could turn out to be something special in the 25 year long research history in ME/CFS. Yes, it’s a small study, but never before has a study on a medication in ME/CFS had these kind of promising results. If it turns out to be true in bigger studies, this is definitely a game changer.

The study on 30 patients showed that 10 out of 15 patients gets a significant improvement from the cancer drug Rituximab who wipes out most of the B-cells in the immune system. 9 out of the 10 responders get a “major improvement” according to the paper. In the placebo group only 2 out of 10 got a significant improvement. The result is then 10-2 between the groups. Or 9-1 if you only look at “major improvers”.

The director of Haukeland University hospital, Stener Kvinnsland, who was not directly involved in the study, said to TV2 that he ”had a strong feeling that this was a breakthrough”. Dr. Kvinnsland is one of Norways most respected cancer researchers with a solid track record, but to the newspaper Bergens Tidende he said that the Rituximab finding is one of the most exciting things he has been allowed to follow in his professional career.

Charles Shepherd, MD and medical advisor to Britains biggest patient association, said to New Scientist that: “It’s the most encouraging drug result so far in the history of this disease. Although it’s a small trial, it’s produced dramatic results.” Recently I attended the IACFS/ME research conference in Ottawa, and I had the opportunity to interview three of the major ME/CFS-experts about their thoughts on Rituximab and ME/CFS. At this time the study in PLoS ONE was not yet published, so the following interviews are based on thoughts and theories they shared without knowing the data yet.

Nancy Klimas, professor in immunology at the University of Miami, has worked on the immune system in ME/CFS for 25 years, and she was very excited about the upcoming study results.

– I think they’re doing fabulous work. I first heard about their work when that first report came out a couple of years ago. I was in London, and I was all excited, I couldn’t wait for them to do this, Klimas said.

She said she wanted to leap right in and do her own study, but she didn’t want to step on the Norwegian researchers toes.

– I decided that I needed to let them do what they did, because they did it right, and they deserve all the credit for all the work that they’re doing – it’s very exciting and very innovative, Klimas said.

But she points out that Rituximab is a “big gun”.

– You’re wiping out all of the B-cell population. So the question in my head about this is – why would it work?

She then presented two possible theories. One is that a big subgroup of ME/CFS-patients has an autoimmune disease that is antibody mediated.

– So this could be, if Rituximab works, an autoimmune disease that is specifically and entirely by an antibody mediated autoantibody. We know that Rituximab is being used in autoimmune diseases like RA, Klimas said.

According to Klimas another possibility is that the B-cell is a reservoir for a virus that really matters. The B-cells are the major reservoir for Epstein Barr Virus, a virus that has been linked to ME/CFS several times in the research literature. It is well established in research that mononucleosis trigger ME/CFS in many cases.

– Let us just pretend it’s EBV for a moment. When we’re done with our EBV, when you and I had our mono, we are left with roughly one million latent EBV-infected cells. And our immune system handles that. One of the questions that have never been answered in chronic fatigue syndrome patients is, do they have a bigger reservoir than that? Was their primary infection so intense that they have ten million or a hundred million latently infected cells? Because there’s going to be a threshold where a normal immune system can’t contain latency – and can’t maintain that virus under control. (…) Maybe Rituximab simply knocked down the reservoir so intensely so that we got it down under the threshold, and then the immune system could handle it. And that would make sense to me, Klimas said. She stressed that this is just a hypothetical construct without data to back it up, and then adds that she would love to see some before and after cells and serum plasma be sent off from the Norwegian freezers to “EBV-wizards” like Ron Glasers group.

– Do you think this is a more likely explanation than autoantibodies?

– We don’t know. All we know is that they got better, and it’s not that many yet. To understand the mechanism of why it works is critical to go forward with that kind of investigation. And remember that the ME/CFS population is not homogenous, they’re not all the same, there’s going to be a subgroup this matters for. So I’m also hoping in the laboratory that they are looking for a biomarker, or at least storing enough stuff so that someone else can look at the biomarkers to predict who responded. Because we might very well discover that it’s a viral load phenomena or that it’s only the autoimmune group that responded. And there are markers for things like that, Klimas said.

– Some people in the ME/CFS research community say all the immune findings in ME/CFS are inconsistent, and by that implies that they’re not so important. What are your comments on that?

– I’m so frustrated by that response because it’s been 25 years. Pull out the study that have very large numbers if you want to get some consistency in the data. Throw out all of the studies that have 20 patients and under, and look at the studies that have 100, 200, 300 patients – and they are saying the same thing. It’s not hard. I think the immunology is proven. It’s not controversial. It’s not a hypothesis. It’s proven. There’s immune activation, there’s cellular dysfunction and there is a significant degree of immune dysfunction, Klimas said.

She says increasingly more research are coming out that are backing up this statement.

– Everything is fitting together, the clinical observations, the biological observations and even the more sophisticated genomics that try to understand mechanisms. It’s all fitting together. So I have no trouble saying with great confidence that the immune system in ME/CFS is not working correctly, Klimas said.

The story behind how Rituximab came to be an important treatment in RA, which Klimas mentions, is definitely worth a look in this context. When two scientists in Britain, Jonathan Edwards and Geraldine Cambridge, came up with their theory about possible B-cell involvement in RA in the 1990s, they were mostly met with a cold shoulder from the rest of the research community. T-cells was then the only “accepted” theory in RA, and therefore everybody automatically thought that the theory of Edwards and Cambridge were not worth pursuing. In this article from The National you can find a short version of this interesting story on how these two scientists, against all odds and more or less single handedly, turned the whole field of RA around.

Back to the conference in Ottawa, where I get hold of Harvard-professor Anthony Komaroff for a chat on Rituximab in ME/CFS. He has followed the ME/CFS-field as a clinician and researcher since the very beginning 25 years ago, and he is one of the main authorities in the field.

– The theory makes sense to me, Komaroff said.

But he hopes the researchers are trying to find biomarkers that can be monitored, to understand what mechanisms in the body that responds to the medication. The researchers in Norway has just got a substantial grant for exactly this kind of work from a philanthropic organization. Their hypothesis is that there’s a central autoimmune component in ME/CFS, and that it might be possible to find a specific autoantibody. If they find this, they will have a biomarker, and this will be a major step in researching the mechanisms behind the disease. But finding an undiscovered autoantibody is like looking for a needle in a haystack, so it’s time consuming work.

Anthony Komaroff says there are plenty of examples in medical history that a drug has effects the medical community didn’t yet know it had, and therefore it’s important to also look at alternative explanations for possible mechanisms.

– A good example is statin drugs. They lower cholesterol, we know that, but it’s now clear that in people with perfectly normal cholesterol with heart disease, the statins really reduce the risk of future heart disease even though they don’t change the cholesterol much because it’s already low. Why? Because the statins also reduce the inflammation inside artherosclerotic plaques. So the statin works by at least two mechanisms in heart disease, and cholesterol is only one. Most people thought it was stupid to do a study on the value of statin in people where cholesterol levels were low because you wouldn’t expect it to work, but it does because it has other effects, Komaroff said.

– What are your thoughts on an autoimmune hypothesis in ME/CFS?

– A number of studies suggest that there are autoantibodies. Autoimmune means that the immune system is confused – that it attacks a tissue that it shouldn’t attack because it is its own self. I think it’s entirely plausible that this attack is mediated because that tissue has within it some foreign infectious agent, and that the attack is perfectly sensible. The immune system is not attacking its own tissue deliberately, it’s attacking its own tissue because it sees something foreign inside that tissue. That’s theoretical, but again there’s some evidence to support it, Komaroff said.

– In addition to finding biomarkers, what’s the next step for this kind of possible treatment in ME/CFS?

– The next question will be, do you have to continue this treatment pretty much for the rest of someones life? And what is the optimal dosing regimen to minimize side effects and still achieve the benefits? But I think it’s a perfectly plausible future form of therapy, Komaroff said.

The findings from Norway in 30 patients are done with the gold standard in medical research on drugs – what is called a double blinded, placebo controlled, randomized study. Placebo controlled means that the patients are divided into two groups – 15 get placebo (salt water) and 15 get Rituximab. Double blinded means that neither the patients, nor the researchers, know who gets real drugs and who doesn’t. Randomized means that it’s random which group the 30 patients end up in.

Of course bigger and better studies on Rituximab in ME/CFS are needed to confirm these findings, but this is a really promising start with a solid study design showing impressive results. The researchers in Norway are already well underway with an open label study to understand more about how the drug works in ME/CFS before they try to design and get a bigger randomized controlled trial up and running.

In Ottawa I also interviewed José Montoya, infectious disease specialist at Stanford University, about this. He’s leading a research initiative at Stanford trying to solve the ME/CFS-enigma, and he’s also part of the massive 10 million dollar Chronic Fatigue Initiative that involves top universities like Harvard, Stanford and Columbia (split second and 12th at the recent World University Rankings). Montoya thinks ME/CFS is the most misunderstood disease of our time, and his goal is no less than eradicating ME/CFS as a problem.

– Are you also looking in the direction of autoimmunity?

– Yes, I’m basically looking for an aberration in the immune system in response to pathogens. My specialty is infectious disease – what infections trigger that abnormal immune response? And I think there is a component of autoimmunity based on the fact that it’s most common in women and many patients get better during pregnancy and often gets worse after birth. And researchers have found autoantibodies in patients with CFS. So I’m expecting an autoimmune component, Montoya said.

– Some people say the immune findings in ME/CFS are inconsistent – what’s your take on that?

– Despite some disagreements, there is a core of findings that are consistent. There is a group of abnormalities that everybody seems to agree on, Montoya said.

He has done interesting findings with the use of antivirals in ME/CFS, and in a pilot study from 2006, 9 out of 12 patients had major improvement in their symptoms.

– I went from the observation that valcyte seems to work, to a double blind that shows that it works in a subgroup of patients. It’s not working on everybody, and now we try to understand why. My hope is to be able to find a marker that will allow me to say “this patient need valcyte, while this patient needs another drug”. So my interest is not valcyte, my interest is helping the patients with CFS through different interventions whatever it takes, Montoya said and adds that the placebo controlled trial he mentions will be published soon.

He says it’s entirely plausible that it’s the immune response to different infections that leads to symptoms, not a virus in itself.

– The thinking behind the pathogen directed therapy we have been doing with valcyte is that we are taking away the excuse for the immune system to attack. Pathogens distort the immune system into overreacting, and I think the solution will be in controlling the pathogen, but also controlling the immune response, Montoya said.

He thinks Rituximab and other immune modulators are candidates for future therapies in ME/CFS.

– The problem is how to identify the patients that would benefit from the intervention. That is the only issue that I have with it, Montoya said and continues:

– There have been autoantibodies that have been found in CFS. What has not been found is the auto antibody or the group of anti autobodies that are exclusive to CFS.

– And this will take time I guess?

– Yes, but what can shorten that time, Montoya asks with a big smile.

– …eh….money?

– Yes, exactly, he says laughing.

He’s on his way back to the mecca of innovation, Silicon Valley, with Stanford University in the heart of it.

– And in Silicon Valley we have always found a solution. So I have decided to do it the Silicon Valley way.